1. Field of the Invention
The present invention relates to the art of non-toxic oxygen transport and contrast enhancement agents for internal and external animal use, and more particularly to stable high concentration fluorocarbon emulsions capable of sterilization and which are selectively free of calcium precipitation, reduce in vivo and in vitro red blood cell, or erythrocyte, injury, reduce anemia effects, and have reduced viscosity and reduced rate of oxidation or free radical damage, particularly of components of the emulsion and of contacted body tissue.
2. Description of the Prior Art
In the past, efforts to use emulsified fluorocarbons as an oxygen transport or carrier, as in a blood substitute, and as a contrast enhancement agent, as for X-ray, ultrasound and magnetic resonance imaging, have encountered certain difficulties. Purity, non-toxicity, chemical and biological inertness and ability to excrete are desirable objectives. The emulsified fluorocarbon must be capable of sterilization, preferably by heat, have long-term size and function stability preferably in the fluid state, be industrially feasible, persist for sufficiently long or effective times in the blood stream when used intravascularly and be eliminated sufficiently rapidly from the body.
For intravenous use, it is considered important to have small particle size. However, long term storage for extended periods of time for a month or longer, of blood substitutes has heretofore resulted in conglomeration or coalescence of the fluorocarbon particles in the emulsion into larger particles, especially after heat sterilization. For a general discussion of the objectives and a review of the efforts and problems in achieving these objectives in fluorocarbon blood substitutes, see "Reassessment of Criteria for the Selection of Perfluoro Chemicals for Second-Generation Blood Substitutes: Analysis of Structure/Property Relationship" by Jean G. Riess, 8 Artificial Organs, 34-56, (1984).
Larger particle sizes are dangerous in intravenous use in that they tend to collect in the lung, liver, spleen and some other organs, enlarging them and endangering their functioning. On the other hand, it is desired to have sufficient particle size in the fluorocarbon particles for them to collect in tumors and other areas when fluorocarbons are used as a contrast enhancement medium. Larger particle sizes within reasonable limits, also, are unobjectionable when used in other, non-venous systems in the body, such as, for example, the cerebrospinal fluid ventricles and cavities.
In the past, it has been observed that fluorocarbon emulsions used intravascularly accumulate disproportionately more in the spleen, as opposed to other organs such as the liver. This concentration in the spleen sometimes causes a transient hypersplenism, a condition characterized by an enlarged and over-active spleen from which a transient anemia results. A fluorocarbon emulsion having the above-indicated characteristics but also having a more even distribution among the major body organs is desired.
Glycerol is normally a good osmotic agent for fluorocarbon emulsions, but in concentrations has been observed to hemolize the red blood cells. The glycerol apparently swells the red blood cells, damaging the cells, promoting the egress of hemoglobin and thus causing damage to the cells. Certain other additives, notably sugars have similar red blood cell damaging effects. It has long been desired to avoid or to limit the amount of such hemolytic agents in the emulsion.
It is known that lecithin and other phospholipids are subject to oxidation in the vascular system. Such oxidation of lecithin phospholipids is also observable in respect to the lecithin phospholipid emulsifier components of stored or packaged fluorocarbon emulsions. It is desired to have effective, stable and non-toxic fluorocarbon emulsions having phospholipid emulsifying agents or other oxidizable components wherein oxidation is inhibited.
It is frequently desired to have high concentration fluorocarbon emulsions, but they unfortunately tend to have high viscosity. It may also be desired to have emulsions containing nutrients, such as glucose and like sugars. Glucose, however, has been known to make fluorocarbon emulsions more viscous. It is desired to have fluorocarbon emulsions that are less viscous and more fluidic, to facilitate packaging, injectability and avoidance of blood vessel blockage.
It has been desired, further, to provide a vehicle carrier for delivering fat or oil soluble and fluorocarbon soluble medicines through the intravascular, intraperitoneal, oral, respiratory, cerebrospinal and other internal animal body tissue or systems, including human tissue, as well as for delivering such medicines externally such as cutaneously through the skin. "Tissue" in this specification will be used to include blood.
It is often desirable to have some emulsions which contain or deliver calcium, and which do not have calcium precipitating components. Many buffers, however, are phosphates or carbonates and form excessive calcium precipitates which not only reduce the amount of calcium available for therapeutic use, but dangerously deposit calcium compounds in the tissue.
The present invention is directed toward improvements in the formulation and use of fluorocarbon emulsions to meet these and other objectives while providing a stable, non-toxic and efficacious fluorocarbon emulsion.